Exceptional ALL Remission Rates With CD19 CAR T-Cells

The use of autologous CD19 chimeric antigen receptor (CAR) T-cells led to exceptional remission rates in patients with relapsed and refractory acute lymphoblastic leukemia (ALL), according to a recent report published in the American Journal of Hematology (2018 Sep 6. Epub ahead of print).

The phase 1b/2 clinical trial that led to the report was conducted by Elad Jacoby, MD, Physician, Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Aviv University, Israel, and colleagues. They administered CD19 CARs produced in-house with a CD28 costimulatory domain in children and young adults with relapsed and refractory ALL who had already received a fludarabine and cyclophosphamide lymphodepleting regimen.

Using Locally Produced CD19 CAR T-Cells

A total of 21 patients with relapsed and refractory ALL were enrolled in the study between July 2016 and March 2018. Patients underwent a single leukapheresis procedure. The primary end points of the trial were production feasibility, patient safety, and best overall response rates.

Patient were eligible for inclusion in the trial if they were aged between 1 and 50 years, did not respond to at least 2 previous therapies, had a CD3 count >250/µl, had no clinical signs of graft-versus-host disease, and no history of immunosuppressive treatment; those who had received previous CD19-directed treatments were also included.

Patients with high disease burden were offered an additional course of chemotherapy before the lymphodepleting regimen—ie, fludarabine, high-dose cytarabine, and granulocyte-colony stimulating factor (FLAG), or bortezomib, vincristine, dexamethasone, and asparaginase (BVDAsp), at the physician’s discretion.

Of the 21 patients in the trial, 20 were considered evaluable. The median age of participants was 11 years. Patients had previously received a median of 4 therapy regimens, including CD19 targeted therapy in 7 (30%) and hematopoietic stem-cell transplant (HSCT) in 10 (48%). Extramedullary leukemic involvement was reported in 8 patients; 7 had active lesions prior to receiving the lymphodepletion regimen and CAR-T therapy.

A total of 14 patients with high disease burden were offered a chemotherapy course before the trial interventions—BVDAsp was administered in 8 patients, FLAG was given to 5, and 1 patient declined treatment.

Promising Remission Rates and Reduced Disease Burden

Findings showed that of the 20 evaluable patients, 18 had in vivo expansion of CAR T-cells. A total of 16 patients developed cytokine release syndrome, and 11 patients had neurotoxicity; no deaths occurred in relation to toxicity. The remission rate was 90%, and included resolution of all refractory extramedullary sites.

Of note, disease burden was reduced in 11 (84%) of the 13 patients who received BVDAsp or FLAG.

According to Dr Jacoby and colleagues, allogeneic HSCTs were referred for all patients who responded to therapy.

“The CAR in this study includes a CD28 costimulatory domain, associated with early and effective activity, but relatively limited persistence in preclinical studies and clinical reports in ALL, including ours. Poor persistence of CD28-based CAR T cells led us to refer all responding patients to an allogeneic HSCT.

Disease relapse occurred in a total of 4 responding patients. The estimated 1-year event-free and overall survival rates were 73% and 90%, respectively.

“[W]e were able to show clinical remissions or relapsed ALL with locally-produced CD19 CAR T-cells. Reducing disease burden prior to CAR T-cells may have contributed to the safety profile and to the clinical outcome in our study,” Dr Jacoby and colleagues concluded.

“Extramedullary disease, including CNS involvement occurring after chemotherapy or immunotherapy, was especially susceptible to CAR T-cells, suggesting that this is a unique indication for this cellular therapy,” they added.—Janelle Bradley